Immediate ADT Improves Survival in Relapsed Prostate Cancer

Roxanne Nelson BSN, RN

May 11, 2016

Treatment given sooner rather than later is more effective in prostate cancer patients who either relapse biochemically after curative therapy or have noncurable disease, according to new randomized, controlled trial findings.

Compared with delayed intervention, receiving androgen-deprivation therapy (ADT) immediately significantly improved overall survival in men with prostate-specific antigen (PSA)-relapsed or noncurable prostate cancer.

Among 293 men in the trial, at a median follow-up of 5 years, 16 (11%) men died in the immediate-therapy arm and 30 (20%) in the delayed-therapy arm.

The 5-year overall survival was 86.4% in the delayed-therapy arm versus 91.2% for those receiving immediate-therapy (log-rank, P = .047).

But the survival benefit with immediate therapy came with a trade-off: a reduced quality of life.

There was greater deterioration of global quality of life in the immediate-therapy arm than the delayed arm during the first 2 years by "a small but clinically notable amount," note the study authors.

However, the patients in the immediate-therapy arm started with a slightly higher global quality-of-life score and the rates of change over time did not statistically differ.

The study was published online May 4 in the Lancet Oncology.

"This will now give us information, for the first time, to discuss with patients facing a new diagnosis that their prostate cancer is now incurable," said lead author Gillian M. Duchesne, MD, a radiation oncologist at the Peter MacCallum Cancer Centre, Melbourne University, Australia.

"Until now, we have not been able to say with any evidence base what the balance would be between having treatment immediately which would cause side effects in an asymptomatic patient, or waiting until the disease causes symptoms that need treatment," Dr Duchesne told Medscape Medical News. "Now we can say immediate is better for survival, it gives some side effects which you can choose to delay if you wish because your medium term outlook is good, but if you have some risk factors, you are better to start now."

Treatment decisions have largely been based on either patient or physician preference. The basis for doing the trial, Dr Duchesne explained, was that no one knew for certain which was better. "Indeed many 'knew' immediate was better and many 'knew' that delayed was better," she said.

"Physician preference remains strong, but we hope this will influence it objectively and patient preference will be easier to give advice on," Dr Duchesne said.

Interpreted With Caution

In an accompanying editorial, Michael S. Leapman, MD, and Peter R. Carroll, MD, both from the University of California, San Francisco, explain that this finding doesn't mean that immediate androgen deprivation should become standard treatment for all patients with biochemical recurrence.

Selecting optimal management for prostate cancer patients who relapse after surgery or radiotherapy as assessed by PSA levels has been the subject of much debate, they point out, and The current study "provides clinicians and their patients with much improved estimates of the potential value of such therapy as well as its trade-offs (ie, reduced quality of life)."

Also, not all research has identified a survival benefit from immediate treatment and patients are increasingly worried about side effects of therapy.

"I do think the results provide more granular information about benefits/risks," explained Dr Carroll. "However, I think the results need to be interpreted with some caution as the patient population may not represent well all those who present with a rising PSA after primary treatment.

"Some of these men may be at a low risk of metastatic relapse and not benefit form ADT, but be exposed to its side effects which are increasingly being recognized as significant," he told Medscape Medical News.

Another factor to consider is that new technology and therapy will refine the timing and type of treatment for this patient population. "I also think that technology is racing into this space to better assess risk, such as circulating cell free DNA," Dr Carroll said.

Study Details

In this study, Dr Duchesne and colleagues conducted a multicenter, phase 3 trial of men with prostate cancer who either had experienced PSA relapse after previous attempted curative therapy or were not considered suitable candidates for curative treatment (261 with PSA relapse and 32 with noncurable disease).

The men were randomized to either the immediate-therapy arm (n = 143) or delayed-therapy arm (n = 151).

The primary outcome was overall survival in the intention-to-treat population, and secondary endpoints included cause-specific survival, time to clinical progression, time to androgen independence (castration resistance), and global quality of life over the first 2 years.

Median follow-up was 5 years from the date of randomization.

Overall survival was superior for men who received immediate therapy, with an unadjusted hazard ratio (HR) of 0.55 for immediate versus delayed therapy (P = .050).

HR was similar after adjustments for study group, planned androgen-deprivation therapy schedule, PSA doubling time, and treatment center (HR, 0.54; P = .074).

In the PSA-relapse group, a total of 40 (15%) men died. Of these, 26 (19%) were assigned to the delayed-therapy arm and 14 (11%) to the immediate-therapy arm. The estimated 5-year overall survival rates were 78.2% in the delayed-therapy arm and 84.3% in the immediate-therapy arm (log-rank, P =.10).

In the other, smaller group (n = 32) of men with noncurable disease, 6 (19%) died; 4 (29%) in the delayed-treatment arm and 2 (11%) in the immediate-treatment arm, and all from nonprostate cancer causes.

Survival analysis was not done because of the small sample size.

The authors note that the times to both local and distant progression were also significantly longer in men who received immediate therapy: 18 (13%) of 140 patients experienced local progression versus 30 (20%) of 150 patients in the delayed-therapy group.

The adjusted HR for time to local progression was 0.51 (P = .001).

In the immediate-therapy arm, 27 (19%) patients had distant progression compared with 30 (20%) in the delayed-therapy arm.

The adjusted HR for time to local progression was 0.51 (P = .001).

Adverse events were similar between the two study groups, with 23 patients experiencing grade 3 treatment-related adverse events.

In addition, 105 (36%) men experienced adverse events requiring hospital admission although none were attributable to treatment or differed between groups.

The most common serious adverse events were cardiovascular, which occurred in 9 (6%) patients in the delayed-therapy arm and 13 (9%) in the immediate-therapy arm.

The study was funded by the Australian National Health and Medical Research Council and Cancer Councils, The Royal Australian and New Zealand College of Radiologists, Mayne Pharma Australia. Several of the authors have declared relationships with industry, as noted in the study.

Dr Carroll has received grants from Genomic Health and Myriad Genetics and personal fees from Genomic Health, Takeda Pharmaceuticals, and Medivation, outside the submitted work. Dr Leapman disclosed no relevant financial relationships.